Systems and methods for detecting complex networks in MRI image data

ABSTRACT

Systems and methods for detecting complex networks in MRI image data in accordance with embodiments of the invention are illustrated. One embodiment includes an image processing system, including a processor, a display device connected to the processor, an image capture device connected to the processor, and a memory connected to the processor, the memory containing an image processing application, wherein the image processing application directs the processor to obtain a time-series sequence of image data from the image capture device, identify complex networks within the time-series sequence of image data, and provide the identified complex networks using the display device.

CROSS REFERENCE TO RELATED APPLICATIONS

The instant application claims priority to U.S. Non-Provisional patent application Ser. No. 16/368,774, filed Mar. 28, 2019, which claims priority to U.S. Non-Provisional patent application Ser. No. 15/997,631, filed Jun. 4, 2018 and issued as U.S. Pat. No. 10,285,658 on May 14, 2019, which claims priority to U.S. Non-Provisional patent application Ser. No. 15/820,338, filed Nov. 21, 2017 and issued as U.S. Pat. No. 10,034,645 on Jul. 31, 2018, which claims priority to U.S. Provisional Patent Application No. 62/485,196, filed Apr. 13, 2017, U.S. Provisional Patent Application No. 62/563,611, filed Sep. 26, 2017, U.S. Provisional Patent Application No. 62/568,676, filed Oct. 5, 2017, and U.S. Provisional Patent Application No. 62/589,452 filed Nov. 21, 2017, the disclosures of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to image processing, including automated image processing, and more specifically to the detection of objects and/or signals within images.

BACKGROUND

Object detection is a key component of many image processing and computer vision systems that enable a computer to locate and classify objects within an image or sequence of images. Classic examples of object detection include facial recognition, and object tracking. Processes for automated image tracking can also be useful for detecting objects or patterns that might not be immediately apparent to human viewers of the image. The ability for computers to perceive and comprehend visual data is key for enhancing the capabilities of computer systems to interact with, and provide feedback on, their environment.

SUMMARY OF THE INVENTION

Systems and methods for detecting complex networks in magnetic resonance imaging (MRI) image data in accordance with embodiments of the invention are illustrated. One embodiment includes an image processing system, including a processor, a display device connected to the processor, an image capture device connected to the processor, and a memory connected to the processor, the memory containing an image processing application, wherein the image processing application directs the processor to obtain a time-series sequence of image data from the image capture device, identify complex networks within the time-series sequence of image data, and provide the identified complex networks using the display device.

In another embodiment, the time-series sequence of image data includes data describing a set of images taken from a specific viewpoint over time.

In a further embodiment, images in the set of images are three dimensional images.

In still another embodiment, identifying complex networks within the time-series sequence of image data includes preprocessing the time-series sequence of image data, detecting structures within the time-series sequence of image data, and measuring connectivity between structures within the time-series sequence of image data.

In a still further embodiment, preprocessing the time-series sequence of image data includes realigning the time-series sequence of image data to a fixed orientation, unwarping the time-series sequence of image data, and despiking the time-series sequence of image data.

In yet another embodiment, a magnetic resonance imaging image processing system, including at least one processor, a memory connected to the at least one processor and containing an image processing application, a display in communication with the at least one processor, synchronization circuitry, a magnetic resonance imaging machine in communication with the synchronization circuitry and the at least one processor, wherein the magnetic resonance imaging machine is directed to obtain image data describing at least a patient's brain, and a stimulus device connected to the synchronization circuitry, wherein the stimulus device is configured to provide a stimulus to a patient, wherein the image processing application directs the processor to obtain the image data from the magnetic resonance imaging machine via a network, generate a time-series sequence of image data of the patient's brain, wherein the time-series sequence of image data is time-stamped with the times of stimuli provided by the stimulus device using the synchronization circuitry, and pre-process the time-series sequence of image data to identify brain regions, generate at least one neurological model, the at least one neurological model including a data structure describing at least one network within the time-series sequence of image data, and metrics specifying neurological activity observable within the time-series sequence of image data, assign a biotype to the patient based on the neurological model, and provide a graphical user interface containing the assigned biotype using the display.

In a yet further embodiment, preprocessing the time-series sequence of image data further includes realigning the time-series sequence of image data, unwarping the time-series sequence of image data, despiking the time-series sequence of image data; and, registering brain structures observable within the time-series sequence of image data and a brain atlas, wherein the brain atlas comprises a data structure stored in the memory and describes physical regions within a reference brain.

In another additional embodiment, despiking the time-series sequence of image data comprises measuring displacement between images in the time-series sequence of image data, and identifying time periods in the time-series sequence of image data where the displacement between images is greater than a frame displacement threshold.

In a further additional embodiment, the atlas is the Automated Anatomical Labeling atlas.

In another embodiment again, at least one of the at least one neurological model is a first level reactivity model, and the metrics specifying the neurological activity specify strength of neuronal activation across brain regions.

In a further embodiment again, the image processing application further directs the processor to generate a first level reactivity model, wherein generating the first level reactivity model includes extracting image data describing brain structures from image data describing non-brain structures in the time-series sequence of image data, removing global signals from the image data using a white noise mask, spatially smoothing the image data using a blurring kernel, and determining a degree of neuronal activation in response to stimuli delivered corresponding to the time-stamps in the time-series sequence of image data.

In still yet another embodiment, the blurring kernel is an 8 millimeter blurring kernel.

In a still yet further embodiment, the at least one of the at least one neurological model is a psychophysiological interaction model, and the metrics specifying the neurological activity specify degree of connectivity between brain regions.

In still another additional embodiment, the image processing application further directs the processor to generate a psychophysiological interaction model from the pre-processed time-series sequence of image data, wherein generating the psychophysiological interaction model includes performing slice time correction on the pre-processed time-series sequence of image data using a descending interleaved acquisition sequence, normalizing the pre-processed time-series sequence of image data to a coordinate system, spatially smoothing the pre-processed time-series sequence of image data using a blurring kernel, defining at least one volume of interest in the pre-processed time-series sequence of image data using a mask, extracting an eigenvariate from the at least one volume of interest, generating a volume of interest data structure including a deconvolved time course including the physiological component of the psychophysiological interaction model, a psychological variable describing a parametric contrast of task onsets from a contrast of interest, and data describing the interaction between the physiological and psychological variables.

In a still further additional embodiment, the at least one neurological model comprises a resting state model.

In still another embodiment again, generating the resting state model including concatenating preprocessed image data across stimuli, segmenting the concatenated image data by tissue types, generating at least one regressor matrix, generating residual images from the segmented preprocessed image data, and bandpass filtering the residual images.

In a still further embodiment again, the tissue types are at least white matter, grey matter, and cerebrospinal fluid.

In yet another additional embodiment, the at least one resting state model is a region of interest resting state model.

In a yet further additional embodiment, the at least one resting state model is a voxel wise resting state model.

In yet another embodiment again, generating the voxel wise resting state model further includes extracting a time-series sequence of image data corresponding to a particular set of stimuli from the segmented time-series sequence of image data, and applying regression against the extracted time-series sequence of image data for a particular set of stimuli against the segmented time-series sequence of image data for all voxels, indicating the overall resting state for each voxel.

In a yet further embodiment again, assigning a biotype includes obtaining a database of biotype classifications including image data annotated with reactivity and connectivity metrics associated with specific biotypes, matching metrics from the resting state model to the best fitting biotype classification.

In another additional embodiment again, the database of biotype classifications is generated using machine learning on a training data set.

In a further additional embodiment again, assigning a biotype includes generating an indicator of fit describing how closely the biotype matches the patient.

In still yet another additional embodiment, the assigned biotype is associated with at least one treatment, and the image processing application further directs the processor to recommend the at least one treatment to the user.

In another embodiment, the at least one treatment is an at least one drug, and a medical professional treats the patient by prescribing the at least one drug to the patient.

In a further embodiment, the image processing application further directs the processor to generate at least one efficacy metric based on the assigned biotype, wherein the at least one efficacy metric indicates the likelihood of success of treating the patient using the at least one drug.

In still another embodiment, the magnetic resonance imaging machine is connected to a first communications port capable of transmitting data over a network, the processor is connected to a second communications port capable of receiving data over the network; and the magnetic resonance imaging machine and the processor are connected via the network using the first communications port and the second communications port.

In a still further embodiment, the stimulus device provides a Go No-Go test battery and an emotional regulation test battery to the patient.

In yet another embodiment, the stimulus device is a visual display device.

In a yet further embodiment, a method for identifying complex networks in time-series sequence of image data, includes obtaining time-series sequence of image data from an image capture device, realigning the time-series sequence of image data to a fixed orientation using an image processing server system, unwarping the time-series sequence of image data using the image processing server system, despiking the time-series sequence of image data using the image processing server system, detecting objects within the time-series sequence of image data using the image processing server system, measuring connectivities between detected objects within the time-series sequence of image data using the image processing server system, matching the measured connectivities between detected objects to at least one complex network stored in a database of complex networks using the processor, and displaying the at least one matched complex network using a display device.

Additional embodiments and features are set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the invention. A further understanding of the nature and advantages of the present invention may be realized by reference to the remaining portions of the specification and the drawings, which forms a part of this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a system diagram illustrating connected components of an image processing system in accordance with an embodiment of the invention.

FIG. 2 is a flow chart illustrating a method for detecting and classifying objects in images in accordance with an embodiment of the invention.

FIG. 3 is a flow chart illustrating a method for performing a test battery in accordance with an embodiment of the invention.

FIG. 4 is a flow chart illustrating a method for providing stimuli in accordance with an embodiment of the invention.

FIG. 5 is a flow chart illustrating a method for preprocessing image data in accordance with an embodiment of the invention.

FIG. 6 is a flow chart illustrating a high level overview of a method for generating reactivity models in accordance with an embodiment of the invention.

FIG. 7 is a flow chart illustrating a high level overview of a method for generating connectivity models in accordance with an embodiment of the invention.

FIG. 8 is a flow chart illustrating a method for preprocessing data for connectivity analysis in accordance with an embodiment of the invention.

FIG. 9 is a flow chart illustrating a method for generating PPI models in accordance with an embodiment of the invention.

FIG. 10 is a flow chart illustrating a method for modeling resting state in accordance with an embodiment of the invention.

FIG. 11 is a graphic illustrating several neural circuit pathways in accordance with an embodiment of the invention.

FIG. 12 conceptually illustrates several biotype neural circuit pathways in accordance with an embodiment of the invention.

FIG. 13 is an illustration of various biotypes in accordance with an embodiment of the invention.

FIG. 14 is an example of a survey rankings in accordance with an embodiment of the invention.

FIGS. 15A, 15B, and 15C are example assessment score reports in accordance with an embodiment on the invention.

FIG. 16 is an illustration of various neural circuit pathways in accordance with an embodiment of the invention.

DETAILED DESCRIPTION

Turning now to the drawings, systems and methods for detecting complex networks such as (but not limited to) neural circuit pathways in image data are discussed. Further, methods for complex network detection within a three-dimensional (3D) matrix of pixel data are disclosed. Object detection within images is a key aspect of machine vision, and allows computers to parse and understand image data. In a time ordered sequence of images (video), object detection over the video can be used to track activity, and enable detection of complex networks. Further, in a larger system where other components can trigger changes in the observed image, time synchronization circuitry can be used to match system activity to observed responses in a series of images.

Enhanced object detection capabilities have numerous applications, including, but not limited to, automation of tagging and classification of objects within images, as well as images themselves. The ability to classify objects allows a computer to perform additional processing, extract additional data, and/or utilize image information in other processing operations. In some cases, object detection can trigger image processing systems to produce warnings, reports, and/or other human-interpretable signals to automatically notify a user.

Network detection methods described below can be used with unconventional image capture systems, and can further be used to allow computer systems to process data in new and unconventional ways. In numerous embodiments, object detection and classification are used to generate a taxonomy of objects. Taxonomies of objects can then be used for rapid analysis of future images. In some embodiments, machine learning techniques can be applied to generate taxonomies.

One of ordinary skill in the art will appreciate that while specific implementations of methods and systems for performing complex network detection are described below, there are numerous embodiments in accordance with the spirit of the invention. While specific discussion will be directed to performing complex network detection within MRI image data, the systems and methods described below can be used to detect complex networks in a variety of types of image data and/or applications.

Image Processing Systems

Image processing systems can be used to acquire image data, process image data, and display processed data. In numerous embodiments, image processing systems are constructed of multiple computing systems. In a variety of embodiments, image processing systems are implemented on a single computing system. Image processing systems can process a wide variety of image data, however certain specific embodiments can be utilized for processing MRI image data.

Turning now to FIG. 1 , a system diagram of an image processing system in accordance with an embodiment of the invention is illustrated. Image processing system 100 has at least one image capture device 110. Image capture device 110 is connected to image processing server system 120 and image processing interface device 130 via network 140. In many embodiments, the image capture device is an MRI imaging device. However, the image capture device can be any device capable of capturing an image as appropriate to the requirements of a given application.

The image capture device can include various peripheral devices, including terminals, display devices, and other interface devices. The image processing server system can be implemented on a personal computer, a server computer system, or any other computing device as appropriate to the requirements of a given application. The image processing interface device can be a personal computer, a tablet computer, a smartphone, a monitor, and/or any other device as appropriate to the requirements of a given application.

Image processing server systems can include a processor, memory, and/or at least one storage system containing an image processing application that includes machine readable instructions that configures the computer to process image data in accordance with methods described below. In some embodiments, the image processing interface device and the image processing server system are on the same platform. The network can be, but is not limited to, the Internet, a local area network, a wireless local area network, wide area network, a software defined network, and/or any other type or combination of types of network as appropriate to the requirements of a given application.

Devices described above can communicate via the network via communications ports. In many embodiments, data is transferred between one or more devices via the network. In a variety of embodiments, data transfer between one or more devices is achieved using physical media transfer, such as a flash drive, compact discs, or any other physical storage media as appropriate to the requirements of a given application.

Once images are obtained by the image capture device, image data describing the captured image can be sent via the network to the image processing server system for analysis. In some embodiments, image data is also sent to the image processing interface device. In numerous embodiments, the image processing server system processes received image data and outputs results to the image processing interface device. In a variety of embodiments, some processing is done by the image processing interface device.

Processed data and/or any other output of the system can be provided to the user by a user interface device. In many embodiments, user interface devices provide graphical user interfaces which enable a user to access data. In many embodiments, the user interface device is connected to the network.

In many embodiments, one or more of the devices on the network incorporate, or have access to, synchronization circuitry. Synchronization circuitry can be used to synchronize image capture with provided stimuli. In numerous embodiments, the image processing interface device is configured to provide stimulus using a stimulus device. In a variety of embodiments, stimulus devices are controlled by the image processing server system, and/or the image capture device. A stimulus device can be a visual display device, such as, but not limited to, a monitor, a virtual reality headset, a projector, and/or any other visual display device as appropriate to the requirements of a given application. A stimulus device can be an audio display device, such as a speaker. Stimulus devices can provide visual stimuli, audio stimuli, tactile stimuli, and/or any other stimuli as appropriate to the requirements of a given application.

While specific network configurations have been described above, one of ordinary skill in the art can appreciate that any configuration or devices could be used as appropriate to the requirements of specific applications. Methods for image processing using image processing systems are described below.

Performing Complex Network Detection in MRI Image Data Using Image Processing Systems

MRI scans of a patient's head yield high quality image data of the patient's brain in a non-invasive manner. While there are many different types of MRI scanning techniques, two categories of MRI scans are the functional MRI (fMRI) and the structural MRI (sMRI). sMRI scans generally acquire 3D image data of a patient's brain, defining the structural anatomy. In many embodiments, sMRI scanning can include different imaging techniques such as, but not limited to, diffusion tensor imaging, or any other specialized scanning technique. fMRI scans are a type of MRI scan that yields time-series sequence of image data describing neuronal activation within the patient's brain. In many embodiments neuronal activation patterns can indicate the degree of connectivity between different regions of the patient's brain. In many embodiments, MRI data is preprocessed to remove artifacts. In a variety of embodiments, neuronal activation patterns can indicate the degree of reactivity to particular stimuli in the patient's brain. Image processing systems can be used to process fMRI data to extract data regarding connectivity and reactivity. Based on connectivity and/or reactivity data, one or more biotypes can be assigned to the patient. Biotypes can be associated with one or more drugs and/or therapies that can be more effective in treating at least one negative symptom that the patient suffers from. In many embodiments, machine learning can be utilized to associate biotypes with specific connectivities and/or reactivities. In a variety of embodiments, support vector machines are used to associate biotypes with specific connectivities and/or reactivities. Systems and methods for associating specific connectivities and/or reactivities with biotypes are described below.

Turning now to FIG. 2 , a process for performing complex network detection in accordance with an embodiment of the invention is shown. Process 200 includes (210) obtaining fMRI scan data, and preprocessing (220) image data. Reactivity metrics are generated (230), connectivity maps are generated (240), and the observed connectivity forms the basis of a complex network classification enabling assignment of a biotype (250) to the observed neural circuit pathways. In some embodiments, a therapy can be recommended (260) based on the assigned biotype. In many embodiments, process 200 is performed by image processing server systems. However, in some embodiments, part or all of process 200 can be performed by image capture devices and/or image processing interface devices. Methods for obtaining image data are described below.

While various processes for identifying and/or classifying complex networks, such as neural circuit pathways, are described above with reference to FIG. 2 , any of a variety of processes can be utilized to identify and classify complex networks using image data as appropriate to the requirements of specific applications in accordance with numerous embodiments of the invention. A number of processes that can be utilized to identify and classify complex networks in accordance with certain embodiments of the invention are discussed below.

Obtaining Image Data

Image data can be obtained using specialized image capture devices, such as MRI machines, that output MRI scan data. In many embodiments, patients are placed inside of MRI machines. Stimuli can be provided via a stimulus device to the patient and their psychophysical responses can be recorded using at least the MRI machine. These responses can be recorded over time using fMRI techniques to generate time-series data. In many embodiments, a resting state fMRI is generated. In a number of embodiments MRI data taken during performance of tasks can be utilized to filter MRI data obtained during periods in which tasks are not being performed to provide a more accurate model of resting state neural circuit activation.

Turning now to FIG. 3 , a method for obtaining image data in accordance with an embodiment of the invention is illustrated. Process 300 includes obtaining (310) a sMRI scan of a patient's brain. Process 300 also includes synchronizing (320) at least one stimulus device with the fMRI device, performing (330) and fMRI scan of the patient's brain while providing (340) stimuli to the patient. In numerous embodiments, the sMRI scan is image data captured by an MRI machine. In a variety of embodiments, the same MRI machine is used to perform the sMRI scan and the fMRI scan. MRI machines can have ancillary components, including connected computing devices that collect and store data from the scanning components of the MRI. In many embodiments, performing an fMRI scan generates a time-series of image data depicting neural activity within the brain of the patient. The time-series sequence of image data can be sets of sets of images, which together show the 3-D structure of the brain. In some embodiments, each image is a 3-D image representing a portion of the brain. A sub-portion of an image is called a voxel. In many embodiments, a single time-series sequence of image data set is generated during the course of an fMRI session. However, in numerous embodiments, several time-series of image data are acquired. In a variety of embodiments, at least one set of time-series of image data is acquired per stimulus battery (task).

Stimuli can be applied to the patient during scanning to measure the effect of the stimuli on neuron activation within the brain. In many embodiments, stimuli are images displayed to the patient. Synchronizing stimuli with the images in the time-series associates the response with the stimulus that caused it. Synchronization of stimulus devices with MRI scanners can be achieved using synchronization circuitry. In numerous embodiments, synchronization is mediated by a software application designed to associate continuous time series image data with a continuous time series stimulus regime. In this way, the image data output by the MRI machine can be processed relative to specific stimuli. In a variety of embodiments, time-series data is generated that is time stamped, where the time stamps are synchronized with time stamps present within image date captured by the MRI machine. In numerous embodiments, the delay between stimulus and the resultant image data time stamp is on the order of 100 milliseconds. In order to correct for delay, stimulus images can be jittered by +/−200 milliseconds. However, any jitter amount can be applied as appropriate to the requirements of given applications. That is, effects of stimuli detected within the image can be correlated to the specific stimulus that caused the response.

While various stimuli and measurement techniques that can be utilized in the detection of complex networks such as, but not limited to, neural circuit pathways are described above with reference to FIG. 3 , any of a variety of stimuli and measurement techniques can be utilized as appropriate to the requirements of a given application in accordance with many embodiments of the invention. Additionally, while systems and methods utilizing MRI machines in accordance with various embodiments of the invention are described above, similar systems and methods can be applied to image data obtained from other image capture devices, such as, but not limited to, computed tomography scanners, positron emission tomography scanners, or any other brain imaging device as appropriate to the requirements of a given application. Methods and types of stimuli are described below.

fMRI Stimuli

Psychophysical responses are dependent upon stimuli provided. Particular stimuli, and the patient's responses can be used to generate diagnostic and treatment data. In many embodiments, diagnostic and treatment data describes a patient's biotype, and/or appropriate treatments tailored to the patient's specific biotype. In many embodiments, correlating particular responses to specific stimuli can be used to generate data. In some embodiments, the particular sequence of stimuli is kept consistent across tests for the same patient. In a variety of embodiments, the particular sequence of stimuli is kept consistent across many patients. The sequence of stimuli can be chosen in such a way as to reduce the likelihood of artifacts

Turning now to FIG. 4 , a method for providing stimulus to a patient in accordance with an embodiment of the invention is illustrated. The method 400 includes performing (410) a Go No-Go test battery, and performing (420) an emotional regulation test battery. In many embodiments, motional test batteries include at least one face test battery. Face test batteries can include, but are not limited to, conscious faces test batteries, nonconscious faces test batteries, or any other emotional regulation task as appropriate to the requirements of a given application. Method 400 further includes performing (430) a resting state analysis.

In many embodiments, Go No-Go test batteries involve providing a series of representations to a patient as stimuli, wherein some representations indicate a “Go” state, and some representations indicate a “No-Go” state. For example, a Go state can be a word, such as, but not limited to, “Press,” and/or a color indicator such as, but not limited to, green. A No-Go state can be a word, and/or a color indicator such as, but not limited to, red. In many embodiments, representations are displayed at predefined intervals. In some embodiments, indicators are displayed for 500 milliseconds, with a 750 millisecond stimulus interval. However, any display and/or stimulus interval duration can be used in accordance with the requirements of a given application.

Faces test batteries can include providing representations of faces representing emotional states. Representations can be placed in a specific, pseudorandom, or random ordering. Conscious face test batteries can display the representations at intervals allowing for conscious recognition by the patient, such as, but not limited to, 500 millisecond display times with 750 millisecond interstimulus delay. Nonconscious face test batteries can be designed in a similar way to conscious face test batteries with backwards masking. An emotional state representation can be displayed for 10 milliseconds, followed by a neural (non-emotion state) representation for 490 milliseconds. However, any time intervals can be used as appropriate to the requirements of given applications. For example, any set of intervals that allows for nonconscious recognition of emotional state representations can be used.

Resting state scans can be acquired by presenting the patient with a black screen, and/or any other neutral, non-task stimuli, and performing an fMRI scan while the patient remains awake. While several tests have been described above with respect to FIG. 4 , one of ordinary skill in the art would recognize that any number of tasks and tests can be used in accordance with the requirements of various applications.

One of ordinary skill in the art will recognize that the tests could be performed in any order, and that no specific ordering is required. Further, not all tests need to be performed. In some embodiments, only a resting state analysis is utilized. Methods for preprocessing acquired image data are described below.

Preprocessing Image Data

Preprocessing image data can be performed by image processing systems to remove artifacts, and prepare the image data for subsequent analysis and processing steps. In numerous embodiments, preprocessing can be used to standardize image data to known reference images. For example, in several embodiments, MRI image data can be preprocessed to yield time-series sequence of image data in which brain structures and/or regions within the preprocessed time-series can be identified by the image processing system. In a variety of embodiments, a machine learning system is utilized to identify brain structures and/or regions using a training dataset of brain images. In a variety of embodiments, the image processing system uses a reference atlas to identify structures.

Turning now to FIG. 5 , a method for preprocessing image data is illustrated. Process 500 includes realigning and unwarping (510) image data. Image data can be despiked (520) with respect to movement and despiked (530) with respect to variance and/or any source of noise artifacts as appropriate to the requirements of a given application. In many embodiments, spikes with respect to variance are the result of extreme responses, such as, but not limited to, periods of very high activity followed by periods of very low activity. Further, process 500 includes applying (540) linear co-registration to identified structures in the image data. Realigning and unwarping image data can be used to remove movement artifacts from a fMRI scan time-series of images. Methods for realigning and unwarping image data that can be used in accordance with several embodiments of the invention can be found in the Statistical Parametric Mapping (SPM) library by the Wellcome Trust Centre for Neuroimaging of University College London, London, England. The manual of SPM version 8 (SPM8) can be found at http://www.fil.ion.ucl.ac.uk/spm/doc/spm8_manual.pdf. However, other processes, including other versions of SPM, such as SPM12 can be used as appropriate to the requirements of a given application.

fMRI image data can be despiked with respect to movement and variance. In many embodiments, the repetition time (TR) can be used to map when spikes occurred. In a variety of embodiments, a frame displacement (FD) threshold is established and used to detect spikes. In some embodiments, an FD threshold of 0.3 mm is used. However, any of a variety of FD thresholds can be used in accordance with various applications of given embodiments of the invention. In numerous embodiments, default variance cut-offs, and spike regressors are generated. Variance cut-offs and/or spike regressors can be utilized when performing later regression steps. In many embodiments, the cut-offs are used to ensure quality data for regression models.

Further, quality control (QC) images and metrics can be generated. For example, scaled and unscaled mean variance images across the time series can be generated. In some embodiments, max variance images across the time series can be generated. In a variety of embodiments, temporal signal to noise ratios can be measured across the time-series. While specific QC images and metrics are described above, any number of different QC metrics could be used in accordance with given applications.

Linear co-registration can be performed using the FSL software library of by the Oxford Centre for Functional MRI of the Brain of the University of Oxford (FMRIB), Oxford, England, including the FMRIB's Linear Image Registration Tool (FLIRT). An online manual for the FSL software package, including FLIRT, and a variety of other programs discussed herein, can be found at (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/). While a specific method for preprocessing image data is described above, any number of steps could be incorporated for preprocessing image data in accordance with the requirements of a given application. Preprocessed data can be used in a variety of ways, including, but not limited to, generating reactivity models and connectivity models. Methods of generating reactivity models are discussed below.

Generating Reactivity Models

Reactivity models can be generated from preprocessed image data. Reactivity models indicate which regions and/or structures of the brain become active and/or reactive in response to a stimulus. In numerous embodiments, reactivity processing is performed region by region in the brain. Reactivity processing can involve generating first level reactivity models. First level reactivity models can include data describing the reactivity of particular regions of interest (ROI) in the brain. ROIs can be individual structures, and/or groups of structures. In many embodiments, reactivity models describe the degree of activity within various regions of the brain. In several embodiments, the degree of activity in a region can be classified as hypoactive, typical, or hyperactive. The activity of particular regions can be utilized to determine effective treatments. Treatments can affect the activity of particular brain regions. In a variety of embodiments, additional processing steps are utilized to prepare the preprocessed image data for analysis.

Turning now to FIG. 6 , a method for generating reactivity models in accordance with an embodiment of the invention is illustrated. Process 600 includes obtaining (610) preprocessed image data. Brain data is extracted (620) and global signals can be regressed (620) out using a white matter mask. The image data can be spatially smoothed (630) and first level reactivity models can be generated (640).

In many embodiments, preprocessed image data is obtained from the memory of an image processing server system. However, preprocessed image data can be obtained from a variety of storage systems, such as, but not limited to, flash drives, random access memory, hard disk drives, solid state drives, SD cards, or any other storage medium as appropriate to the requirements of a given application. Brain data can be extracted from preprocessed image data in such a way that non-brain tissue can be removed from the image. In a variety of embodiments, the Brain Extraction Tool (BET) of the FSL software package can be used to perform brain extraction. However, any of a variety of structure detection methods can be used to extract non-brain material from images, including, but not limited to, edge detection, greyscale matching, gradient matching, corner detection, ridge detection, Hough transforms, structure tensors, feature description algorithms, and/or any other feature detection algorithm as appropriate to the requirements of given applications.

Global signals can be removed via regression using a white noise mask. In a variety of embodiments, the white noise mask is warped into the native space of the image data being processed. The image data can be smoothed by applying a blurring kernel across each image in the time-series. In a variety of embodiments, a blurring kernel of 8 millimeters is utilized. However, any number of different kernel sizes can be used as appropriate to the requirements of a given application. In a variety of embodiments, nuisance regressors are applied to remove additional spikes. First level reactivity models can be generated from the image data. In many embodiments, first level reactivity models describe neuron activation, including varying degrees of activation such as hypo, typical, and hyper activation in response to specific stimuli.

While a specific method of generating reactivity models is illustrated above, one of ordinary skill in the art would appreciate that the recited processes could be performed in different orders, or some processes may be added or omitted as appropriate to the requirements of a given application. In addition to generating reactivity models, preprocessed data can be used to generate connectivity models. Methods for generating connectivity models are described below.

Generating Connectivity Models

Connectivity models can describe the connections between various regions of the brain. In some cases, neuronal connections between regions are underdeveloped, typically developed, or overdeveloped. In a variety of embodiments, connectivity models and reactivity models describe complex networks. However, complex networks can contain information from just reactivity models, or just connectivity models in accordance with the requirements of a given application. In several embodiments, connectivity models are generated from preprocessed image data. In many embodiments, pre-processed image data can be passed through additional connectivity preprocessing steps to enable creation of accurate connectivity models from captured MRI data. Various connectivity models and metrics can describe how signals from different regions and/or structures of the brain of the patient are transmitted.

In many embodiments, the organization of the connections between various brain structures and/or regions can be used to indicate responsiveness to various psychoactive chemicals. Connectivity models and metrics can include psychophysical interaction (PPI) models, ROI resting state models, and voxel wise resting state models. PPI models can describe connectivity between a ROI and other brain regions, thereby indicating the brain regions where the activity depends on the psychological context and the physiological state of the ROI. Resting state models are used to estimate the resting state of a particular ROI, or a region defined by a voxel or set of voxels. Methods for performing connectivity analysis are described below.

Turning now to FIG. 7 , a method for performing connectivity analysis in accordance with an embodiment of the invention is illustrated. Process 700 includes obtaining preprocessed image data. Preprocessed image data can be obtained in a similar manner as describe above with respect to reactivity models. Process 700 further includes generating (720) PPI models, and performing (730) secondary processing for resting state modeling. ROI resting state models can be generated (740) and voxel wise resting state models can be generated (750). Methods for performing additional connectivity preprocessing steps are described below.

Connectivity Preprocessing

Preprocessed image data can be passed through additional connectivity preprocessing steps to enable accurate measurements of time-series data. Connectivity preprocessing can include mapping the image data to a coordinate system in order to define regions of the brain. Turning now to FIG. 8 , a process for performing connectivity preprocessing in accordance with an embodiment of the invention is described below.

Process 800 includes obtaining (810) preprocessed image data. Slice time correction can be performed (820) and image data can be normalized (830) to a coordinate system. The image data can further be smoothed (830).

In many embodiments, slice time correction can be achieved using a given number of slices with a repeat time (TR) of 2.5 seconds and a descending interleaved acquisition sequence. In some embodiments, the given number of slices is 40, however any number of slices could be used in accordance with the requirements of a given application. Slice time correction can help correct for error introduced by non-simultaneous slice recording during a scanning iteration. Further, when the image data is normalized to a coordinate system, a variety of coordinate systems can be used. In many embodiments, the Montreal Neurological Institute (MNI) coordinate system is used. However, numerous other coordinate systems could be used, including, but not limited to, the Talairach coordinate system. Additionally, spatial smoothing can be performed similarly to the methods described above with respect to relativity analysis. In a variety of embodiments, once connectivity preprocessing has occurred, connectivity models can be generated. Furthermore, first level general linear models (GLM) can be initialized. Methods for generating PPI models are described below.

Generating PPI Models

PPI models can be used to determine which neuronal activations in a brain at a given time are dependent on a given stimulus. PPI analysis gives insight into the functionality of an individual's brain. In many embodiments, the FEAT program of the FSL software package can be used to generate PPI models. However, any number of programs and/or packages can be used to generate PPI models as appropriate to the requirements of a given application.

Turning now to FIG. 9 , a process for generating PPI models in accordance with an embodiment of the invention is illustrated. Process 9 includes obtaining (910) preprocessed connectivity image data. The eigenvariate of the time series is extracted (920) from the volume of interest (VOI), and a VOI data structure is generated (930).

In many embodiments, the VOI is defined by a mask. In a variety of embodiments, the VOI is defined by a masked that is anatomically-derived. Anatomically-derived masks can be spheres that mask out specific regions of the brain. However, any shape of mask, including complex three-dimensional structures can be used as appropriate to the requirements of a given application. In numerous embodiments, the mask used to define the VOI masks out regions that are not in a ROI. The eigenvariate of the time series from the VOI can be extracted using the SPM8 library. In some embodiments, extracting the eigenvariate further includes obtaining a specific task. In a variety of embodiments, extracting the eigenvariate includes obtaining a specific mask. In many embodiments, extracting the eigenvariate includes obtaining a contrast number from a first level GLM. Generating a VOI data structure can include a deconvolved time course containing only the physiological component of the PPI, the psychological variable describing the parametric contrast of task onsets from the contrast of interest, and the interaction between the physiological and psychological variables. This data structure can function as the PPI model. In numerous embodiments, nuisance regressors are used from the first level GLM. While a specific method of generating a PPI data structure has been described above, any number of additional variables can be used as appropriate to the requirements of a given application. Connectivity preprocessed image data can be further utilized to generate resting state models. Methods for generating resting state models are described below.

Generating Resting Models

Resting state models can be used to determine the default resting state of the brain. The default resting state can give insight into the normal level of reactivity for a particular region of the brain for the individual in question. Hypo, typical, or hyper activation between different regions can give valuable insight into both brain related disorders, and potential treatment methods.

In many embodiments, resting state models are acquired by performing fMRI scans on a patient who is instructed to perform no tasks, and is not provided any stimuli. In a variety of embodiments, resting state models can be generated using fMRI data acquired during a test battery. Residual images can be generated using the test battery fMRI data, which can be used to generate a model of the patient's resting state. Image data acquired during various tasks can be useful in helping isolate neural activation observed during intervals in which tasks are not being performed, but that is task related. In this way, neural circuit pathways activated during resting state can be better separated from activations that are artifacts arising from the challenges of maintaining patients in a true resting state during imaging. While removal of such artifacts typically results in more informative neural circuit pathway classification, neural circuit pathway classification can be performed using processes without, or with minimal artifact removal.

Turning now to FIG. 10 , a process for generating resting state models in accordance with an embodiment of the invention is illustrated. Process 1000 includes obtaining (1010) connectivity preprocessed image data, and concatenating (1020) preprocessed image data across tasks. Segmentation is performed (1030), and a task and nuisance regressors matrix is generated (1040). Residual images are generated (1050) using the regressors matrix, and the residual images are filtered (1060). Voxel wise resting state models are generated (1070) and ROI resting state models are generated (1080).

In many embodiments, time-series data is generated for each task provided to the patient. Time-series data can be concatenated to form a single time-series image sequence. In many embodiments, concatenation is performed by appending successive time-series to a chosen first time series. Segmentation can be performed on the time-series in order to segment the structural images into white matter, grey matter, and cerebrospinal fluid (CSF) probability maps. In many embodiments, segmentation is performed using the FAST program from the FSL library. In order to optimize segmentation, white matter and CSF masks can be eroded from the edges inward for several iterations in order to ensure that the masks are capturing correct tissue matter. In a variety of embodiments, erosion can be performed using the SPM library. In many embodiments, three iterations are applied, however any number of iterations can be applied in accordance with the requirements of a given application. The segmented time-series sequence of image data can be warped into coordinate space defined by the Montreal Neurological Institute (MNI space), and additional masking can be applied to fine tune segmentation. For example, a mask can be used to remove additional grey matter from the white matter segment as a result of the erosion. In many embodiments, the mask is an atlas from the AAL Single Subject Atlas set provided by the Montreal Neurological Institute. Once segmentation has been performed, the mean time-series for each segment can be stored and/or provided.

A regressor matrix can be generated for use with the segmented time-series. In many embodiments, the regressor matrix includes some or all of: task regressor information, including a constant to indicate overall task effects; spike regressor information; realignment parameters, and their temporal derivatives and their squares; and white matter and CSF time-series across all tasks. Residual images can be generated by running regression to move the variance associated with a particular task, movement, and white matter/CSF noise using the generated regressor matrix. Residual images can then be filtered by bandpass filtering. In many embodiments, a high frequency cutoff of 0.009 Hz and a low frequency cutoff of 0.08 Hz is used. However, different cut-offs can be used as appropriate to the requirements of a given application.

Resting state models can be generated using the filtered images. Voxel wise resting state models can be generated by extracting the time-series for a specific task, and regressing against the time-series from all voxels in the brain. Fisher tests, Z-transforms, and/or a time-series across a brain atlas can be generated, indicating the overall resting state for each voxel. ROI resting state models can be generated by using the DPABI toolbox by The R-fMRI Network, which can be found at http://rfmri.org/dpabi. As noted above, the ability to develop resting state models using information concerning task related activation of voxels can assist with removal of artifacts resulting from the challenges of a patient maintaining a true resting state during imaging. In many embodiments, however, resting state models are built using only data obtained while a patient is not receiving stimuli.

Resting state models can be used to identify neural circuit pathways that correspond to biotype classifications. In many embodiments, specific patterns of reactivity and connectivity can be used to classify the presence of a specific complex in the observed data. In the context of MRI data the specific complex network classifications can be referred to as biotype classifications, and medication information to treat a given reactivity imbalance can be issued using the image processing system. An example of biotype classification is discussed below.

Biotype Classification

Neural circuit pathway circuits revealed by image processing systems in accordance with various embodiments of the invention can be used to automatically identify and/or classify the presence of complex networks that can be referred to as biotypes. In numerous embodiments, machine learning is used to automatically identify and/or perform biotype classification based upon observed resting state neural pathway circuits. In some embodiments, a support vector machine is used to automatically perform biotype classification. In several embodiments, convolutional neural networks are used to perform biotype classification. A database can be used to train machine learning systems to identify and classify specific biotypes based on observed neural activation and connectivity. In many embodiments, the database is made of MRI image data annotated with complex network classifications, and/or any other type of training data can be used as appropriate to the requirements of a given application. Data in the database can be collected using standardized data collection procedures, including, but not limited to, standardized stimuli order, standardized stimuli time, standardized image processing, and/or any other standardization technique as appropriate to the requirements of a given application.

Biotype classifications can be assigned by analyzing the connectivity and reactivity between regions of the brain. In many embodiments, resting state models are used to assign biotype classifications. Resting state models can contain a set of numbers representing the strength of connection between regions of the brain. Regions of the brain can be associated with various neural circuits. In numerous embodiments, approximately 50 regions are selected for analysis, however a larger or smaller number of regions can be used in accordance with the requirements of a given application. The average strength of the connections over the selected regions are compared to baseline measurements. Based on the average strength of the connections, a determination can be made as to whether or not the neural circuitry is behaving normally or abnormally. In a variety of embodiments, abnormality is determined using a threshold. The threshold can be a specific strength, a predefined number of standard deviations from the norm, and/or any other criterion as appropriate to the requirements of a given application.

Normal and/or abnormal circuits can be used to assign at least one biotype. In many embodiments, assigning biotype classifications using abnormal circuits is performed using a heuristic. In some embodiments, a ranking system is used. In a variety of embodiments, a machine learning algorithm is used. The machine learning algorithm can learn how to weight the importance of specific regions when determining how to assign biotypes. In a number of embodiments, a profile approach is utilized. A profile approach can include matching a patient's observed neural circuit pathways to a database of known neural circuit pathway profiles. A patient may be assigned one or more biotypes. In many embodiments, patients neural circuit pathways can appropriately be classified as an amalgam of biotype classifications. In some embodiments, the image processing system provides the biotype classifications that a patient's resting state neural circuit pathways most closely matches. Provision of biotype classifications can include an indicator of fit, indicating how closely the patient matches a given biotype. The indicator of fit can be a percentage, a statistical estimate, or any other indicator in accordance with the requirements of a given application.

Connections between various regions in the brain that are responsible for the brain performing a set of different physiological and/or psychological functions can be defined as neural circuit pathways. Neural circuit pathways can be mapped and stored in a taxonomy, and/or brain atlas. Turning now to FIG. 11 , a set of example neural circuit pathways are illustrated in accordance with an embodiment of the invention. Deviations in reactivity in specific regions, and/or connectivity can disrupt the normal function of the neural circuit pathways. Hypo, typical, and hyper activity and/or connectivity states can be correlated to specific neurological issues that can be expressed as mental disorders. Turning now to FIG. 12 , a chart illustrating the interplay between connectivity and reactivity in accordance with an embodiment of the invention is illustrated. Brain images showing the neural circuitry for the default mode, salience, negative affect, positive affect, attention, and cognitive control are illustrated, as well as example conditions (rumination, anxious avoidance, negative bias, threat dysregulation, anhedonia, context insensitivity, inattention, and cognitive dyscontrol) and their respective abnormal connectivity and reactivity are illustrated. While specific neural circuit pathways are illustrated in FIG. 12 , numerous neural circuit pathways exist as complex networks within the brain and can be identified and/or assigned in accordance with the requirements of a given application.

Image processing systems can generate image data representing a patient's brain to produce similar outputs using reactivity and connectivity models. Patient biotype can further be displayed as a radar plot as illustrated in FIG. 13 . In many embodiments, scores can be generated that represent the various connections and reactions in neural tissue. In a variety of embodiments, scores can be generated which represent the various circuits that cause particular symptoms. In numerous embodiments, data, such as scores, obtained images, processed images, biotype classifications, and/or any other type of data collected or generated by image processing systems can be provided to the user. In a variety of embodiments, data is provided via a user interface device. However, any number of devices and methods can be used to provide data to a user in accordance with a given application. Turning now to FIGS. 14, 15A, 15B, and 15C, scoring sheets in accordance with an embodiment of the invention are illustrated. In some embodiments, scores can be accompanied by a description of the particular biotype. In many embodiments, score reports and biotype assignment are automatically performed by the image detection system based on the connectivity and reactivity data. In numerous embodiments, only a resting state fMRI is needed to assign biotypes. Based on assigned biotypes, specific drugs and/or drug classes can be recommended to regulate dysfunction caused by the abnormal neural circuitry. Methods for assigning drugs are described below.

Assigning Drugs Based on Biotype

In many embodiments, specific complex networks within the brain (i.e. biotype classifications) as identified by the image processing system can be used to assign drugs to remediate the patient. Different drugs and drug classes affect different chemical issues within the brain. By identifying the abnormal circuitry, and how it is behaving abnormally, specific drugs therapies and mental health therapeutic techniques can be recommended in order to target the specific neural circuit pathways likely responsible for particular behavioral tendencies. Turning now to FIG. 16 , examples of specific therapies that affect specific neural circuits in accordance with an embodiment of the invention are illustrated. In many embodiments, the image processing system can be integrated with a drug database that describes the function of particular psychoactive medication. Image processing systems can assign drugs based on their physiological effects to remediate the identified abnormal circuitry. In some embodiments, machine learning is utilized to refine the effect of particular therapies on biotypes, and/or amalgams of biotypes. In some embodiments, therapies can be stored in a database, such as, but not limited to, a brain atlas, a taxonomy, a drug database, or any other data structure as appropriate to the requirements of a given application. In many embodiments, therapies stored in a database are associated with at least one biotype and/or neural circuit.

In numerous embodiments, doctors treat patients using methods suggested by image processing systems. In a variety of embodiments, patients are scanned using MRI machines. The resulting scan data can be used by image processing systems to assign biotypes. Biotypes can be associated with one or more treatments and/or drug therapies, which can be administered to the patient. In numerous embodiments, biotypes and/or scores can be used to generate an efficacy metric describing efficacy of a particular drug and/or class of drugs on the particular patient. Efficacy metrics can be used to predict treatment outcomes for patients for particular treatments. In numerous embodiments, efficacy metrics are used to recommend a particular treatment with the highest likelihood of success.

Although the present invention has been described in certain specific aspects, many additional modifications and variations would be apparent to those skilled in the art. In particular, any of the various processes described above can be performed in alternative sequences in order to achieve similar results in a manner that is more appropriate to the requirements of a specific application. It is therefore to be understood that the present invention can be practiced otherwise than specifically described without departing from the scope and spirit of the present invention. Thus, embodiments of the present invention should be considered in all respects as illustrative and not restrictive. 

What is claimed is:
 1. A method for recommending personalized treatment protocols for mental health conditions, comprising: obtaining a functional scan of a patient's brain; classifying the patient's brain with a biotype using a neurological model, where the classification is based upon whether each brain network of a plurality of brain networks is hyper active, typically active, or hypo active, and where the plurality of brain networks comprises: default mode, salience, negative affect, positive affect, attention, and cognitive control networks; selecting a treatment protocol from a database based on the biotype, where the database comprises associations between treatment protocols and biotypes; and recommending the selected treatment protocol for treatment of a mental health condition of the patient.
 2. The method of claim 1, wherein the selected treatment protocol is a drug.
 3. The method of claim 1, wherein the selected treatment protocol is a behavioral therapy.
 4. The method of claim 1, wherein the selected treatment protocol is a neuromodulation therapy.
 5. The method of claim 1, further comprising: classifying the patient's brain with a second biotype using the neurological model; and selecting the treatment protocol from the database based on both the biotype and the second biotype.
 6. The method of claim 1, further comprising: calculating an efficacy metric reflecting an estimated likelihood of success of application of the selected treatment protocol to the patient; and providing the efficacy metric.
 7. The method of claim 1, wherein the functional scan of the patient's brain is a functional magnetic resonance imaging scan.
 8. The method of claim 1, further comprising providing a visualization of the biotype, where the visualization indicates relative connectivity in a plurality of neural circuits of the brain.
 9. The method of claim 8, wherein neural circuits in the plurality of neural circuits are selected from the group consisting of: default mode; salience; negative affect; positive affect; attention; and cognitive control.
 10. The method of claim 1, wherein the treatment protocol comprises a plurality of treatment modalities.
 11. A personalized mental health treatment recommendation system, comprising: a processor; and a memory, the memory storing an application configuring the processor to: obtain a functional scan of a patient's brain; classify the patient's brain with a biotype using a neurological model, where the classification is based upon whether each brain network of a plurality of brain networks is hyper active, typically active, or hypo active, and where the plurality of brain networks comprises: default mode, salience, negative affect, positive affect, attention, and cognitive control networks;; select a treatment protocol from a database based on the biotype, where the database comprises associations between treatment protocols and biotypes; and recommend the selected treatment protocol for treatment of a mental health condition of the patient.
 12. The system of claim 11, wherein the selected treatment protocol is a drug.
 13. The system of claim 11, wherein the selected treatment protocol is a behavioral therapy.
 14. The system of claim 11, wherein the selected treatment protocol is a neuromodulation therapy.
 15. The system of claim 11, wherein the application further configures the processor to: classify the patient's brain with a second biotype using the neurological model; and select the treatment protocol from the database based on both the biotype and the second biotype.
 16. The system of claim 11, wherein the application further configures the processor to: calculate an efficacy metric reflecting an estimated likelihood of success of application of the selected treatment protocol to the patient; and provide the efficacy metric.
 17. The system of claim 11, wherein the functional scan of the patient's brain is a functional magnetic resonance imaging scan.
 18. The system of claim 11, wherein the application further configures the processor to provide a visualization of the biotype, where the visualization indicates relative connectivity in a plurality of neural circuits of the brain.
 19. The system of claim 18, wherein neural circuits in the plurality of neural circuits are selected from the group consisting of: default mode; salience; negative affect; positive affect; attention; and cognitive control.
 20. The system of claim 11, wherein the treatment protocol comprises a plurality of treatment modalities. 